Aberrant activation of NLRP3 inflammasome in colonic macrophages strongly associates with the occurrence and progression of ulcerative colitis.Although targeting NLRP3 inflammasome has been considered to be a potentia...Aberrant activation of NLRP3 inflammasome in colonic macrophages strongly associates with the occurrence and progression of ulcerative colitis.Although targeting NLRP3 inflammasome has been considered to be a potential therapy,the underlying mechanism through which pathway the intestinal inflammation is modulated remains controversial.By focusing on the flavonoid lonicerin,one of the most abundant constituents existed in a long historical anti-inflammatory and anti-infectious herb Lonicera japonica Thunb.,here we report its therapeutic effect on intestinal inflammation by binding directly to enhancer of zeste homolog 2(EZH2)histone methyltransferase.EZH2-mediated modification of H3 K27 me3 promotes the expression of autophagy-related protein 5,which in turn leads to enhanced autophagy and accelerates autolysosome-mediated NLRP3 degradation.Mutations of EZH2 residues(His 129 and Arg685)indicated by the dynamic simulation study have found to greatly diminish the protective effect of lonicerin.More importantly,in vivo studies verify that lonicerin dose-dependently disrupts the NLRP3-ASC-pro-caspase-1 complex assembly and alleviates colitis,which is compromised by administration of EZH2 overexpression plasmid.Thus,these findings together put forth the stage for further considering lonicerin as an anti-inflammatory epigenetic agent and suggesting EZH2/ATG5/NLRP3 axis may serve as a novel strategy to prevent ulcerative colitis as well as other inflammatory diseases.展开更多
基金supported by the Program of the National Natural Science Foundation of China(No.81903885,Qi LvNo.21877062,Yinan Zhang+2 种基金No.82073719,Lihong Hu)the program of the Jiangsu“Shuang Chuang”team(No.20182036,Lihong Hu and Yinan Zhang,China)the key research projects of Jiangsu Higher Education(No.18KJA360010,Yinan Zhang,China)
文摘Aberrant activation of NLRP3 inflammasome in colonic macrophages strongly associates with the occurrence and progression of ulcerative colitis.Although targeting NLRP3 inflammasome has been considered to be a potential therapy,the underlying mechanism through which pathway the intestinal inflammation is modulated remains controversial.By focusing on the flavonoid lonicerin,one of the most abundant constituents existed in a long historical anti-inflammatory and anti-infectious herb Lonicera japonica Thunb.,here we report its therapeutic effect on intestinal inflammation by binding directly to enhancer of zeste homolog 2(EZH2)histone methyltransferase.EZH2-mediated modification of H3 K27 me3 promotes the expression of autophagy-related protein 5,which in turn leads to enhanced autophagy and accelerates autolysosome-mediated NLRP3 degradation.Mutations of EZH2 residues(His 129 and Arg685)indicated by the dynamic simulation study have found to greatly diminish the protective effect of lonicerin.More importantly,in vivo studies verify that lonicerin dose-dependently disrupts the NLRP3-ASC-pro-caspase-1 complex assembly and alleviates colitis,which is compromised by administration of EZH2 overexpression plasmid.Thus,these findings together put forth the stage for further considering lonicerin as an anti-inflammatory epigenetic agent and suggesting EZH2/ATG5/NLRP3 axis may serve as a novel strategy to prevent ulcerative colitis as well as other inflammatory diseases.
